Racemic betaxolol is a β-adrenoreceptor antagonist with a pharmacological and pharmacokinetic profile for the treatment of chronic cardiovascular diseases like glaucoma. The disease glaucoma is characterized by the progressive damage to the optic nerve caused by the increased pressure within the eye. Glaucoma is a serious disease of the eye, which may lead to the loss of peripheral vision and if untreated total blindness.
β-adrenoreceptor antagonist (β-blockers) are popularly used to lower intraoccular tension, other conditions of increased intraoccular pressure and management of essential hypertension. The principle effect of β-adrenoreceptor blocker is to reduce cardiac activity by diminishing or preventing β-adrenoreceptor stimulation i.e. by reducing the rate and force of contraction of the heart.
Betaxolol belongs to aryloxypropanolamine class of drugs having a specific action on the cardiovascular receptor sites. Most of the drugs in this series contain one chiral carbon centre but generally administered as racemates. Pharmacological studies have shown that an organism often reacts in a different way when it interacts with each enantiomer of the same molecule. This has promoted the growth of both the switch from the use of racemic drug to single enantiomer drug and innovation the manufacturing processes to make enantiomerically pure molecules with low cost. Although most of the β-blockers are sold as racemates, only S-isomer is associated with β-blocking activity, while the R-isomer is usually responsible for side effects. (Hussian S. S. et al, Toxiocol, 1989, 12) 
The pharmacological characteristics of S-(−)-Betaxolol (Levobetaxolol) of formula 2, a single active isomer of betaxolol exhibited a higher affinity at cloned human β-1 than at β-2 receptors while R-(+)-Betaxolol (Dextrobetaxolol) of formula 3 was much weaker at both receptors. Levobetaxolol was 89-times β-1 selective vs. β-2. Levobetaxolol is more potent than Dextrobetaxolol at inhibiting isoproterenol induced CAMP production in human nonpigmented ciliary epithelial cells and exhibited a micro molar affinity for L-type Ca2+ channels. In conclusion, levobetaxolol is a potent, high affinity and β-1 selective 10P lowering β1 adrenoreceptor antagonist.
The processes employed for the preparation of betaxolol involved protecting the phenol functional group so that the alcohol functionality can be alkylated. The resulting protection and deprotection steps extend the length of synthesis.
Manoury et al., (U.S. Pat. No. 4,252,984) describe preparation of betaxolol by the benzylation of the phenolic alcohol of 4-hydroxyphenethanoic acid. The ester group is then reduced to alcohol 2-(4-benzyloxyphenyl)ethanol which is then condensed with cyclopropyl methyl halide to yield cyclopropyl methyl2-(4-benzyloxyphenyl) ether. This is then debenzylated and treated with epichlorohydrin to yield the compound, which on treatment with isopropylamine gives the betaxolol.
U.S. Pat. No. 4,760,182 by Ippolito et al., teaches the conversion of 4-hydroxyphenethanol to a phenoxide anion with a base and then reaction with epichlorohydrin to yield 1-(4-(2-hydroxyethyl)phenoxy)2,3-epoxypropane.
Wang et al., (U.S. Pat. No. 5,731,463) describe selective alkylation of 4-hydroxy phenethanol via an oxygen dianion to produce an intermediate, which on reaction with epichlorohydrin and subsequent addition of isopropylamine produces betaxolol.
Synthesis of S-(−)-betaxolol of formula 2 has been reported by alkylation of phenol derivative of formula 10 with S-(−)-2-phenyl-3-isopropyl-5-hydroxymethyl oxazolidinyl tosylate of formula 11 followed by the acid catalyzed hydrolysis (Philippe M. Manoury; Jean L. Binet; Jean Rousseau; J. Med. Chem. 1987,30,1003–1011.). 
The enantiomers of betaxolol have been prepared via lipase catalyzed kinetic resolution of racemic drug (Giuseppe Di Bono; Antonio Scilimuti; Synthesis, 699, June1995). The racemic drug on treatment with acetic anhydride afforded N,O-bisacetylated derivative which was hydrolyzed enantio-selectively using PPL or lipase K-10. Alternatively trans esterification reaction was performed using vinyl acetate as the acyl doner on the key intermediate 1-chloro-3-[4(2-cyclopropylmethoxy)ethyl]-phenoxy propan-2-ol.
Drawbacks:
The asymmetric synthesis starting from oxazolidinone derivative of formula 11 involves number of steps. R-glyceraldehyde is converted to the required oxazolidinone derivative in four steps. R-glyceraldehyde is not very stable compound and not commercially available, although it can be prepared from the cleavage of D-mannitol-1,2,5,6-bisacetonide on treatment with lead tetraacetate or sodium periodate among other methods.
The chemoenzymatic route involves either lipase catalyzed hydrolysis or transesterification but the optical purity up to 80% was noted which needs recrystallisation of hydrochloride to improve ee to ˜90%. The overall yield is moderate up to 50%.
In all the above processes cyclopropylmethyl halide has been employed for introducing cyclopropyl group as a reactive intermediate. The cyclopropylmethyl halide, is expensive, highly lachrymetric and unstable. These limitations make the reported processes economically unviable and difficult to scale up.
Therefore it is necessary to develop a short, simple, an economically viable alternative process for S-(−)-betaxolol wherein the use of cyclopropylmethyl halide is avoided, steps involving protection and deprotection are avoided and also product with improved enantiomeric purity is obtained.